Additional Resources

The Tenth Edition of Koda-Kimble and Young’s Applied Therapeutics: The Clinical Use of Drugs includes additional resources for

both instructors and students, available on the book’s companion website at http://thepoint.lww.com/AT10e.

STUDENT RESOURCES

Students who have purchased Koda-Kimble and Young’s Applied

Therapeutics: The Clinical Use of Drugs, Tenth Edition have access

to the following additional resources for each chapter:

 An audio recording of that chapter’s core principles

 A full online reference list for that chapter

In addition, at least one of the following supplements each chapter to enhance the chapter content:

 Audio files (most recorded by author)

 PowerPoints (most created by author)

 PowerPoints with audio (most created/recorded by author)

 Animations

 Videos (some created by author)

 Additional content (created by author)

 Interactive versions of the algorithms found in the book

 Full-color images

INSTRUCTOR RESOURCES

Approved adopting instructors will be given access to the following additional resources:

 PowerPoint slides

 Image bank (includes all images and tables in the book)

 Pathophysiology image collection

In addition, purchasers of the text can access the searchable Full

Text On-line by going to the Koda-Kimble and Young’s Applied

Therapeutics: The Clinical Use of Drugs, Tenth Edition website at

http://thepoint.lww.com/AT10e. See the inside front cover for

more details, including the passcode you will need to gain access

to the website.

v

and personnel trained to evaluate and address anaphylaxis is

prudent.

LATEX ALLERGY

Natural latex is a milky fluid consisting of extremely small particles of rubber obtained from the rubber tree. Natural rubber

includes all products made from, or containing, natural latex.133

Many products commonly used in health care (e.g., gloves, BP

cuffs, catheters, injection ports, rubber stoppers of medication

vials) are made wholly or in part of latex. Over the past several

years, the significance of latex allergy has become clear as cases of

allergic reactions, some life-threatening, have been reported.133

Health professionals must recognize the types of reactions latex

can cause and must know how to minimize patient exposure to

latex. Also, preparing parenteral drugs for latex-allergic patients

can be difficult because of the number of materials involved that

may contain latex.

Health professionals are at significant risk for general, allergy suppression should be reserved for prevention of mild reactions that

are known or strongly suspected to be IgE mediated.30,137

Desensitization

β-LACTAMS

CASE 3-9

QUESTION 1: K.A. is a 24-year-old primigravida in her

eighth week of pregnancy with a history of angioedema

secondary to penicillin. Her initial pregnancy screening

revealed a positive Venereal Disease Research Laboratory

reaction and a fluorescent treponemal antibody absorption

titer of 1:64. K.A. denies a history of genital lesions, currently does not exhibit clinical signs or symptoms of syphilis,

and denies previous treatment for syphilis. Based on the

serologic evidence and her history, a diagnosis of early

latent syphilis is made. Current treatment guidelines indicate that penicillin is the drug of choice for K.A. How can a

possible reaction to penicillin be prevented in K.A.? Is premedication an alternative to preventing a reaction?

There are situations where a drug is medically necessary in

a patient with a known or suspected allergy to the drug, alternative therapy is not available, and diagnostic testing does not

exist. In such cases there are two options: induction of tolerance (also called desensitization) or a graded challenge. Desensitization is the process of administering gradually increasing

doses of a drug in an effort to modify a patient’s response to the

drug so that it can then be safely administered.7 This process

has been used successfully to manage both immune-mediated

and non–immune-mediated reactions. A graded challenge (also

called incremental test dosing) is the process of careful administration of sub-therapeutic doses of drug to determine if a patient

is truly allergic. Although similar sounding, there are distinct differences between the two processes.7 For example, unlike induction of tolerance, a graded challenge does not alter a patient’s

response to the drug. The initial drug doses used for inducing tolerance are sub-allergenic—as low as 1/10,000th of the final dose

and the process can take several hours involving multiple doses,

each slightly larger than the preceding dose. Starting doses for

a graded challenge may be 1/100th of the final dose. The process generally involves fewer steps (as few as two) and can be

typically accomplished more rapidly. If the graded challenge is

completed and a therapeutic course of drug tolerated, a graded

challenge is not required before future courses of the drug. Tolerance induction, on the other hand, is only maintained as long

as the patient receives the suspect drug; any interruption of therapy will require the desensitization procedure to be repeated (see

Case 3-9, Question 4).

The choice of drug desensitization or using a graded challenge

depends on the likelihood of the patient having a true allergic

reaction. A graded challenge may be appropriate in patients with

a distant or unclear history of drug allergy; when the reaction

seems minor or for which diagnostic testing is unavailable; or in

cases where cross-reactivity is expected to be low. For example,

a patient with a maculopapular rash to ceftriaxone may undergo

a graded challenge to imipenem-cilastatin to assess tolerance.

On the other hand, a patient with a well-described, severe IgEmediated reaction to a drug may be better suited for tolerance

induction. Importantly, graded challenge or tolerance induction

should not be used in patients with a history of a severe non-IgE–

mediated reaction such as hepatitis, hemolytic anemia, StevensJohnson syndrome, toxic epidermal necrolysis, or DRESS syndrome due to the risk of provoking a potentially life-threatening

reaction.7 Because K.A.’s reaction to penicillin may be potentially severe, premedication is not an option and desensitization

to penicillin should be started. (See Chapter 69, Sexually Transmitted Diseases, for alternative therapy.)

CASE 3-9, QUESTION 2: How should K.A. be desensitized?

Why should she be skin-tested before desensitization?

If possible before tolerance induction is begun, K.A. should be

skin-tested (see Case 3-1, Questions 3 and 4) to confirm her penicillin allergy.30,40,137 Patients who have a positive history of penicillin allergy, but whose skin tests are negative, can receive full

therapeutic doses without desensitization with little risk of developing an allergic reaction. One author, for example, reported only

one case of acute anaphylaxis in a skin test–negative patient given

full therapeutic doses of penicillin in more than 1,500 skin tests;

similar results have been reported by other investigators.40,137 If

skin testing cannot be performed or if K.A.’s skin test is positive,

desensitization should be initiated. Acute oral desensitization to

penicillin and other β-lactam antibiotics is well established; one

such protocol is outlined in Table 3-12, although others have

been used successfully.138

The oral route for β-lactam desensitization is preferred to

the parenteral route because: (a) exposure by the oral route is

less likely to cause a systemic allergic reaction than parenteral

exposure; (b) fatal anaphylaxis from oral β-lactam drug therapy is rare; (c) preformed polymers and conjugates of penicillin

major and minor determinants toPenicilliumproteins are not well

absorbed after oral administration; (d) blood levels rise gradually,

favoring univalent haptenation; and (e) fatal or life-endangering

TABLE 3-12

β-Lactam Oral Desensitization Protocol

Stock Drug

Concentration Dose Amount Drug Dose Cumulative

(mg/mL)a

No. (mL) (mg) Drug (mg)

0.5 1b 0.05 0.025 0.025

0.5 2 0.10 0.05 0.075

0.5 3 0.20 0.10 0.175

0.5 4 0.40 0.20 0.375

0.5 5 0.80 0.40 0.775

5.0 6 0.15 0.75 1.525

5.0 7 0.30 1.50 3.025

5.0 8 0.60 3.00 6.025

5.0 9 1.20 6.00 12.025

5.0 10 2.40 12.00 24.025

50 11 0.50 25.00 49.025

50 12 1.20 60.00 109.025

50 13 2.50 125.00 234.025

50 14 5.00 250.00 484.025

a

Dilutions using 250 mg/5 mL of pediatric suspension.

b

Oral dose doubled approximately every 15 to 30 minutes.

Dosing for the oral protocol is arbitrary and should be adjusted for individual

patients based on the clinical sensitivity and the desired drug dose end point.

Source: Sullivan TJ et al. Desensitization of patients allergic to penicillin using

orally administered beta-lactam antibiotics. J Allergy Clin Immunol. 1982;69:275;

Wendel GD Jr et al. Penicillin allergy and desensitization in serious infections

during pregnancy. N Engl J Med. 1985;312:1229.

63Anaphylaxis and Drug Allergies Chapter 3

TABLE 3-13

β-Lactam Intravenous Desensitization Protocol

Stock Drug

Concentration Dose Amount per 50 mL Cumulative

(mg/mL)a No.b (mg/mL)c Drug (mg)

0.005 1 0.0001 0.005

0.025 2 0.0005 0.030

0.125 3 0.0025 0.155

0.625 4 0.0125 0.780

3.125 5 0.0625 3.905

15.625 6 0.3125 19.530

31.25 7 0.625 50.780

62.50 8 1.25 113.280

125.00 9 2.5 238.280

250.00 10d 5.0 488.280

a Stock drug solutions are prepared using serial dilutions of the desired goal (e.g.,

500 mg of β-lactam). Doses 1 through 5 represent fivefold dilutions; doses 6

through 10 represent twofold dilutions.

b Interval between doses is 1 to 30 minutes. If desensitization is interrupted for

>2 half-lives of the β-lactam, desensitization should be repeated. c Mix 1 mL of stock drug solution in 50 mL 5% dextrose/0.225 normal saline or

other compatible solution. Infuse each dose for 20–45 minutes. Dilution volume

may vary with patient age and weight.

d If all 10 doses are administered and tolerated, the remainder of a full

therapeutic dose of the β-lactam should be administered.

Dosing for the IV protocol is arbitrary and should be adjusted for individual

patients based on the clinical sensitivity and the desired drug dose end point.

Source: Borish L et al. Intravenous desensitization to beta-lactam antibiotics.

J Allergy Clin Immunol. 1987;80(3 Pt 1):314.

reactions have not occurred using current methods. In addition,

oral desensitization can be accomplished over several hours.30 If

oral desensitization is not possible (e.g., if oral absorption is questionable), parenteral desensitization can be instituted. Although

the subcutaneous and intramuscular routes have been used, the

IV route is quicker and allows better control over the rate and

concentration of drug administered, and any untoward reaction

can be detected promptly and treated rapidly.30,139 Table 3-13 outlines an IVβ-lactam desensitization protocol. Oral and parenteral

desensitization methods have not been compared formally, however. Patients should not be premedicated before desensitization,

because this may prevent detection of minor allergic responses

that may precede more serious reactions. In addition, only experienced personnel should undertake desensitization in an appropriate setting where emergency resuscitative equipment is readily available because severe reactions can develop.137 Thus, K.A.

should undergo oral desensitization as outlined in Table 3-12

if her skin test is positive or if skin testing cannot be performed.

CASE 3-9, QUESTION 3: Is K.A. at risk for an allergic reaction during tolerance induction? If tolerance induction is successful, is she at risk for a reaction during full-dose penicillin

therapy?

Acute β-lactam desensitization, regardless of the route or

protocol chosen, is not without risk. Approximately 5% of

patients experience mild cutaneous reactions during desensitization, although one study reported reactions in 20% of patients

during oral desensitization.30,140 If a reaction occurs during the

desensitization procedure itself, the reaction may be treated and

desensitization continued using lower doses, increased intervals

between doses, or both, after the reaction has abated. Severe,